Association of PM_2.5 Exposure and Alzheimer Disease Pathology in Brain Bank Donors-Effect Modification by <i>APOE</i> Genotype.

Abstract

Fine particulate matter (PM_2.5) exposure has been found to be associated with Alzheimer disease (AD) and is hypothesized to cause inflammation and oxidative stress in the brain, contributing to neuropathology. The <i>APOE</i> gene, a major genetic risk factor of AD, has been hypothesized to modify the association between PM_2.5 and AD. However, little prior research exists to support these hypotheses. This study investigates the association between traffic-related PM_2.5 and AD hallmark pathology, including effect modification by <i>APOE</i> genotype, in an autopsy cohort. A cross-sectional study was conducted using brain tissue donors enrolled in the Emory Goizueta AD Research Center who died before 2020 (n = 224). Donors were assessed for AD pathology including the Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC) score. Traffic-related PM_2.5 concentrations were modeled for the metro-Atlanta area during 2002-2019 with a spatial resolution of 200-250 m. One-year, 3-year, and 5-year average PM_2.5 concentrations before death were matched to participants' home address. We assessed the association between traffic-related PM_2.5 and AD hallmark pathology and effect modification by <i>APOE</i> genotype, using adjusted ordinal logistic regression models. Among the 224 participants, the mean age of death was 76 years, and 57% had at least 1 <i>APOE</i> ε4 copy. Traffic-related PM_2.5 was significantly associated with the CERAD score for the 1-year exposure window (odds ratio [OR] 1.92; 95% CI 1.12-3.30) and the 3-year exposure window (OR 1.87; 95% CI 1.01-3.17). PM_2.5 was also associated with higher Braak stage and ABC score albeit nonsignificantly. The strongest associations between PM_2.5 and neuropathology markers were among those without <i>APOE</i> ε4 alleles (e.g., for the CERAD score and 1-year exposure window, OR 2.31; 95% CI 1.36-3.94), though interaction between PM_2.5 and <i>APOE</i> genotype was not statistically significant. Our study found traffic-related PM_2.5 exposure was associated with the CERAD score in an autopsy cohort, contributing to epidemiologic evidence that PM_2.5 affects β-amyloid deposition in the brain. This association was particularly strong among donors without <i>APOE</i> ε4 alleles. Future studies should further investigate the biological mechanisms behind this association.